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Clinical Review

ACE Inhibitors in Congestive Failure Theodore R. Kantner, MD Lubbock, Texas

Despite improved understanding of both mech­ nin-- system. In addition, some anisms and the quality of care, congestive studies indicate that ACE inhibitors may improve (CHF) remains a serious clinical problem. The tradi­ symptoms and survival. Recent evidence suggests that tional treatments, and digitalis, continue to in patients with mild to moderate CHF, ACE inhibitor play a major role in the management of many patients and a should be administered with or w ithout with CHF; however, in the last decade, angiotensin­ digitalis to achieve the maximum clinical benefit. converting enzyme (ACE) inhibitors have been added Key words. Angiotensin-converting enzyme inhibitors; as an important treatment option. These agents coun­ heart failure, congestive. teract the overstimulation effects of diuretics on the rc- / Tam Tract 1992; 35:305-314.

Congestive heart failure (CHF) is a serious and growing output, in turn, triggers a number of interrelated hor­ clinical problem. Although our understanding of the monal and neurohormonal responses designed to in­ disease process has improved over the last several dec­ crease volume and systemic to ades, the incidence of CHF has increased, w'hile the maintain of major organ systems. However, survival rate has not substantially improved. There are hormonal and neurohormonal overstimulation contrib­ approximately 3 million existing cases and 400,000 new' utes to decompensation, perpetuating the downward spi­ cases of CHF each year in the United States.12 The ral of heart failure. 5-year survival rate of patients treated wfith the traditional One of the most important of these responses is regimen of diuretics and digitalis glycosides remains less activation of the -angiotensin-aldosterone (RAA) than 50%.3 4 Development of new, more effective treat­ system, which is primarily stimulated by reduced perfu­ ments for CHF has therefore been a medical priority. sion of the .5-7 As a result, renin is released, and The purpose of this review is to briefly summarize angiotensinogen is converted to the physiologically inac­ the pathophysiology of CHF and to discuss the major tive angiotensin I. The angiotensin-converting therapeutic interventions, addressing especially the enzyme then transforms angiotensin I into the potent emerging evidence for the utility of the angiotensin­ vasoconstrictor angiotensin II. In addition to increasing converting enzyme (ACE) inhibitors in this difficult vascular resistance, angiotensin II also stimulates the treatment situation. This review focuses on the most secretion of aldosterone from the adrenal glands.5 The common cause of heart failure, which results from sys­ release of aldosterone causes an increase in tolic left ventricular dysfunction. due to the retention of sodium and water and excretion of potassium.1-6 The resulting arterial increases im­ Overview of Pathophysiology pedance to left ventricular ejection, further impairing cardiac performance, and also limits blood flow to skel­ In congestive heart failure due to systolic dysfunction, etal muscles, leading to .8 The sodium-retentive , left ventricular performance, effects of aldosterone result in increases in blood volume and arc reduced. The decline in cardiac and left ventricular filling pressure, contributing to pul­ monary edema.5-8 This increase in blood volume also raises atrial filling pressures and contributes to peripheral Submitted, revised, February 13, 1992. edema. From the Department of Family Medicine, Texas Tech University Health Sciences Other biochemical and metabolic changes observed Center, Lubbock, Texas. Requests for reprints should be addressed to Theodore R. in heart failure include increases in the levels of circulat­ Kantner, M D, Department of Family Medicine, Texas Tech University Health Sciences Center, Lubbock, T X 79430. ing catecholamines1-9 and plasma ,1-10 and

© 1992 Appleton & Lange ISSN 0094-3509 The Journal of Family Practice, Vol. 35, No. 3, 1992 305 ACE Inhibitors in Congestive Heart Failure Kantner

Causal Factors patients.13-14 In addition, diuretics can stimulate the RAA system, producing markedly increased plasma renin and angiotensin II activity, with concurrently raised plasma aldosterone levels.1516 Diuretic therapy may also stimulate the sympathetic , causing an increase in circulating levels.15’16 These stimulatory effects can further increase systemic vascular t Systemic Vascular 4 Cardiac Output resistance and reduce cardiac output, thereby exacerbat­ Resistance () ing the vicious circle of heart failure.5 A large percentage of patients who are adequately controlled initially begin t Blood Volume () T LVED Pressure to experience clinical deterioration within months when managed on diuretic monotherapy.13 These limitations indicate that although diuretics continue to be highly useful in CHF, they may not represent optimal treatment when used alone.

Figure 1. Vicious circle of heart failure. Decreased cardiac Digitalis output causes stimulation of the renin-angiotensin-aldosterone system and aldosterone release. The resultant vasoconstriction After more than 200 years of clinical use, the efficacy and and increased systemic vascular resistance eventually act to safety of digitalis glycosides in all degrees of CHF remain perpetuate heart failure. LVED denotes left ventricular end- controversial.5’17 The usefulness of digitalis has been diastolic pressure; RAAS, renin-angiotensin-aldosterone sys­ demonstrated in severe heart failure and in cases where tem; SNS, sympathetic nervous system. (From Faxon.1 Re­ is a complication of CHF.5’18 Conflict­ printed with permission from the American Heart Journal.) ing data have been reported concerning the use of digi­ talis in the treatment of patients with mild to moderate decreases in plasma levels of and vasodilatory CHF and normal sinus rhythm. Several controlled trials prostaglandins.1 All of these responses may be useful to have found the to be effective in the treatment of compensate for acute heart failure; however, they are some patients with chronic heart failure in normal sinus deleterious in chronic heart failure, leading to progres­ rhythm.19-20 In contrast, placebo-controlled, double- sively declining myocardial function and organ perfusion blind investigations by Fleg et al21’22 did not demonstrate (Figure l).1 The degree of activation of the ncurohor- any noticeable effect of on symptoms in patients monal system has been shown to be inversely related to with mild CHF. Further, whether discontinuation of prognosis in patients with CHF.511 digoxin in mild CHF leads to clinical deterioration has not been established.21-23-24 An additional consideration in the decision to institute treatment with digitalis gly­ Principal Treatments cosides in CHF is their potential for arrhythmic ef­ fects.25-27 Sudden cardiac death, presumably due to ven­ Diuretics tricular arrhythmias, is the terminal event in approximately 40% of patients with CHF.26 Digitalis Diuretic therapy remains a key component of treatment sensitizes the heart to low concentrations of potassium, a for all classes of heart failure. These agents stimulate risk factor for the development of arrhythmias.26 The excretion of sodium and water, thereby reducing pulmo­ assessment of digitalis may be complicated because dig­ nary congestion and improving dyspnea and edema. Po­ italis toxicity can occur in some patients at drug levels tent loop diuretics, such as furosemide and bumetanidc, generally regarded as safe, whereas in other patients even are preferred in patients with severe heart failure, whereas elevated levels of digitalis may not produce symptoms of oral may suffice for patients with milder condi­ toxicity or ECG abnormalities.5’28 Finally, an association tions.5 A can also be used in combination between digitalis and increased mortality in patients who with a or mctolazone (a quinazolinc) to achieve have had a has been reported.29’30 an added effect.512 Despite these conflicting studies, in general the data Despite their considerable value in CHF, there are a suggest that digitalis remains a valuable therapeutic agent number of serious considerations regarding the use of for relieving symptoms and improving exercise perfor­ diuretic therapy. Diuretics may deplete electrolytes and mance and left: ventricular function in patients with con­ increase the risk of ventricular arrhythmias in susceptible gestive heart failure.31 It has been suggested, however,

continued on page 309 306 The Journal of Family Practice, Vol. 35, No. 3, 1992 ACE Inhibitors in Congestive Heart Failure Kantner

O— o Placebo (n = 26) o—o Placebo (n - 25) A— A C a p to p ril (n = 46) A— A (n > 43)

Significantly < baseline (P < .05) ■“ Significantly < baseline (P < .001) Significantly < baseline (P < .01)

Baseline Weeks of Therapy Baseline Weeks of Therapy Figure 2. New York Heart Association (NYHA) functional class ratings (left) and exercise tolerance (right) for patients treated with captopril or placebo in addition to digoxin and diuretics. (From Captopril Multicenter Research Group.34 Reprinted with permission from the Journal of the American College of .) that digitalis should be co-administercd with an agent with captopril, 54% were in the New York Heart Asso­ that has been shown to improve survival in this patient ciation (NYHA) functional class III, 44% were in class population, such as an ACE inhibitor.13 II, and 2% were in class IV.35 Clinical improvement was noted in 80% of patients treated with captopril, com­ pared with only 27% of patients given placebo (P < ACE Inhibitors .05).34 Mean improvement in NYHA class, exercise tol­ erance, and was significantly better In the United States, the ACE inhibitors captopril and among patients who received captopril (Figure 2). Im­ have been approved by the Food and Drug provements in specific symptoms of Cl IF, such as dysp­ Administration (EDA) for the treatment of CHF when nea, orthopnea, fatigue, and edema, were also signifi­ added to digitalis and diuretics. Captopril can also be cantly greater in the captopril group (P < .05 to P < added to diuretics alone when administration of digoxin .001). This study demonstrated that patients with mild is not feasible. A number of other of this class are to moderate heart failure who are already receiving a currently under study. The bulk of the current informa­ diuretic with digitalis may benefit substantially from tile- tion concerning the efficacy and safety of ACE inhibitors addition of an ACE inhibitor to their therapeutic regi­ in CHF is drawn from studies of the prototype agent, men. captopril. Although the usefulness of ACE inhibitors in severe heart failure is well documented,32-33 data con­ cerning their value in mild to moderate heart failure have Captopril Compared with Digoxin in Patients only recently become available. Receiving a Diuretic An important comparison of benefits with an ACE in­ Captopril Added to Diuretic-Digoxin Therapy hibitor vs digitalis in the treatment of patients with mild In a placcbo-controllcd multiccntcr study of patients to moderate CHE was undertaken in a large 6-month with heart failure refractory to diuretic and digitalis ther­ trial conducted by the Captopril-Digoxin Multicenter apy,34 50 patients had captopril (75 to 300 mg per day) Research Group.17 In this study, 300 patients with mild added to their baseline therapy of digitalis and diuretics, CHE (mainly NYHA class II) receiving stable diuretic- while 42 patients (control group) received placebo in therapy were assigned on a double-blind basis to addi­ addition to their existing regimen. Of the patients treated tional treatment with captopril, digoxin, or placebo.

The Journal of Family Practice, Vol. 35, No. 3, 1992 309 ACE Inhibitors in Congestive Heart Failure Kantner

ACE inhibitors directly blunt neurohormonal overstim­ ulation, a factor that appears to be deleterious in patients with heart failure. These findings also underscore the synergistic value of concurrent diuretic and ACE inhibitor therapy in CHF. While providing beneficial hemodynamic effects, ACE inhibitors counteract a number of the deleterious effects caused by diuretic-induced activation of the RAA system. Moreover, ACE inhibitors can reduce the loss of electrolytes, blunt the overstimulation of neurohor­ mones, minimize or prevent potassium depletion, and reduce the potential for diuretic-induced ventricular ar­ rhythmias.13 Figure 3. Numbers of ventricular premature beats (VPBs) at baseline and endpoint for patients with >10 VPBs per hour at baseline treated with captopril, digoxin, or placebo during Survival and Disease Progression Studies maintenance diuretic therapy. P < .05 vs digoxin. (From the Captopril-Digoxin Multicenter Research Group.17 Reprinted ACE inhibitors have been proven both to increase sur­ with permission from JAMA. Copyright 1988, American Med­ vival and to ameliorate symptoms on a long-term basis in ical Association.) patients with heart failure.13 The results of an analysis reported by Furberg and Yusuf37 of over 2000 cases from 24 randomized trials indicate that of all vasodilators Compared with the placebo group (ic, those on diuretics tested, patients treated with ACE inhibitors have the alone), captopril (75 to 150 mg/d) significantly im­ lowest associated mortality rate. In the CONSENSUS proved both exercise time (P < .05) and NYHA func­ trial,38 253 patients with severe CHF (class IV) received tional class (P < .01), whereas digoxin did not. Digoxin their regular therapy—diuretics, digitalis, and vasodila­ increased ejection fraction significantly compared with tors (eg, , prazosin, )—to which cither captopril and placebo (P < .05). The number of ventric­ cnalapril or placebo was added. At the end of 20 months ular premature beats (VPBs), however, decreased by of treatment, the mortality rate in the enalapril group was 45% in the captopril group but did not change signifi­ significantly (P = .003) reduced by 27% as compared cantly in the digoxin group among patients with more with the placebo group38'39 (Figure 4). A report on the than 10 VPBs per hour at baseline (Figure 3). Patients follow-up data obtained 8 Vi months after the end of the receiving placebo (ie, only diuretic therapy) had a greater CONSENSUS trial strongly supported the original data incidence of treatment failure and a significantly (P < on reduction of mortality and also showed enalapril to .05) greater number of hospitalizations and emergency have a longer duration of effect than previously department visits compared with those in either the reported.40 captopril or digoxin groups. Patients in the placebo In another prospective trial,41 addition of captopril group also required increased dosages of diuretics to or an —hydralazine combination was control their heart failure symptoms, compared with compared in 106 patients being evaluated for heart trans­ patients receiving captopril or digoxin. plant. Although both drug regimens were titrated to In another large study among 116 patients with achieve comparable hemodynamic effects, the addition of NYHA class II or III heart failure, Heck et al36 admin­ captopril therapy improved survival compared with the istered either captopril, 25 mg twice daily, or digoxin, isosorbide dinitratc—hydralazine combination. In this 0.1 mg twice daily. All patients also received hydrochlo­ study, ACE inhibitor therapy was shown to be an inde­ rothiazide, 50 mg/d. Over 12 months of therapy, the pendent predictor of survival (P = .015). Similarly, the group treated with captopril demonstrated statistically recent second Veterans Administration Cooperative significant improvements in cchocardiographically deter­ Vasodilator—Heart Failure Trial (V—HcFT II) compared mined diameters, exercise tolerance, and NYHA class, a regimen of enalapril added to digoxin and diuretic compared with patients treated with digoxin. therapy with the addition of hydralazine and isosorbide These results support previous reports of an incre­ dinitrate in patients with chronic congestive heart fail­ mental benefit with the addition of low doses of captopril ure.42 Two-year mortality was significantly (P = .016) to diuretic therapy. They also indicate that captopril can lower with cnalapril (18%) than in the hydralazinc- be an effective and safe alternative to digoxin in patients isosorbidc dinitratc group (25%). Lower mortality was with mild to moderate CHF who are taking diuretics. primarily the result of a reduced incidence of sudden

310 The fournal of Family Practice, Vol. 35, No. 3, 1992 ACE Inhibitors in Congestive Heart Failure Kantner

o— o Placebo captopril group. The difference was statistically signifi­ cant (P < .1). Sudden cardiac death was the terminal event in eight patients assigned to placebo, compared with the sudden death of only one patient treated with captopril (P < .05). The efficacv of captopril in preventing or slowing the progression of left ventricular dilatation following mvocardial infarction (MI) has also been investigated in clinical trials. In a placebo-controlled study among pa­ tients with an initial anterior MI,44 end-diastolic volume Days from Initiation of Therapy increased significantly (P < .2) in the placebo group but not in the group treated with captopril. Moreover, cap­ topril attenuated additional ventricular dilatation in a subgroup of patients with a greater risk of this adverse process. (Patients with ventricular dilatation in the first year after MI had a significantly worse prognosis than other post-MI patients.) In another study,45 patients who had experienced a Q-wavc MI were treated with captopril, furosemide, or placebo. Captopril decreased left ventricular end-systolic volume index significantly (P < .05) compared with furosemide, whereas ventricular volume was significantly increased during treatment with the diuretic or placebo over the 12-month study period. The potential for improved survival in post-MI pa­ tients with left ventricular dysfunction is being further examined in large, multicenter, controlled trials of both captopril4* and enalapril.47 The Survival and Ventricular Months Enlargement (SAVE) study evaluated the efficacy of cap­ Figure 4. Survival over time in patients with moderate to severe topril in improving survival and in reducing cardiovas­ heart failure treated with an ACE inhibitor—captopril39 or cular mortality and the incidence of major deterioration enalapril38—or placebo added to digoxin and diuretics. (Adapt­ ed from Newman, et al,39 with permission from the American in ejection fraction in post-MI patients.46 Results of this Journal of Medicine, and from the CONSENSUS Trial Study trial are forthcoming. The Studies of Left Ventricular Group38 with permission from The New England Journal of Dysfunction (SOLVD) trial47 involved a randomized, Medicine.) double-blind, placebo-controlled protocol designed to assess whether the addition of enalapril to conventional death, an effect that had not been previously demon­ therapy would reduce mortality in patients with conges­ strated. tive heart failure and a low ejection fraction ( s 0.35). A retrospective review of clinical trials involving Most patients (90%) were in NYHA classes II and III. patients with CHF, including patients with NYHA After an average follow-up of 41.4 months, the difference classes II, III, and IV, indicates that captopril added to in survival significantly (P = .0036) favored enalapril. digoxin and diuretics has a favorable effect on survival. In Few studies have carefully examined quality-of-life a report by Klcbcr ct al,43 170 patients with mild CHF indicators while studving ACE inhibition in patients (NYHA class II) received either captopril or placebo with CHF. In a small group of refractory patients placed twice daily over diurctic-digoxin background therapy for on captopril therapy, Dzau and associates48 reported a mean observation period of 2 V2 years (range 3 months improvement in NYHA functional class in all patients, to 5 years). Although there was no statistical difference in along with significant decreases in both hospital admis­ overall mortality between groups, there was a marked sions (P < .005) and hospital days (P < .02) during the reduction in progression of CHF to class IV or death period of study (Figure 5). (14.0% vs 32.4%), and a significantly (P < .12) higher event-free survival rate (1547 vs 1308 days) with capto­ Practical Considerations with ACE Inhibitors pril than with placebo. In another trial among 105 pa­ tients treated with captopril or placebo,39 the mortality Of all the ACE inhibitors available, captopril has been rate was 21% in the placebo group and only 4% in the the most widely studied to date. Studies with other ACE

The Journal of Family Practice, Vol. 35, No. 3, 1992 311 ACE Inhibitors in Congestive Heart Failure Kantner

NYHA Number of Number of gested that longer-acting agents should be used cau­ Class Admissions Hospital Days tiously in patients with severe CHF.56 Nevertheless, these concerns must be balanced against convenience and the potential for increased compliance offered by longer- acting agents.

Other Agents for Congestive Heart Failure In addition to the agents specifically approved by the FDA for the treatment of CHF, numerous other drugs may be useful. Many new agents from various chemical classes are being studied as well, but none is considered a first-line drug for CHF at this time. Oral nitrates and a-adrcnergic antagonists, such as prazosin, produce initial beneficial effects in CHF; how­

Captoprll ever, development of tolerance and consequent loss of efficacy has been reported with both of these groups of Figure 5. Effects of captopril added to digoxin, diuretics, and vasodilators on New York Heart Association (NYHA) class, agents.57 Hydralazine and related vasodilators dilate re­ number of hospital admissions, and number of hospital days in sistance blood vessels and increase cardiac output, but patients with congestive heart failure refractory to conventional they may fail to produce sustained hemodynamic benefits therapy. Patients were followed for longer than 3 months. on a long-term basis and they have a high incidence of (From Dzau et al.48 Reprinted with permission from The New troublesome side effects, such as and England ]oumal of Medicine.) edema.57 Calcium channel blockers may also have poten­ tially beneficial dilating effects on resistance vessels. Their inhibitors,49 however, show effects similar to those ob­ inhibitory effects on calcium transport, however, can served with captopril in CHF, and a favorable effect on concurrently produce significant cardiodepressant effects, survival has also been demonstrated with enalapril.38-42-47 and they are not currently regarded as important future Because orally administered enalapril must be con­ drugs for CHF.57 verted in vivo to its active metabolite cnalaprilat, peak Another group of drugs with which there is some hemodynamic effects of enalapril are not seen until ap­ experience in CHF is the phosphodiesterase inhibitors. proximately 6 hours after dosing.50-51 In a study of pa­ Amrinonc is the prototype drug of the class, and numer­ tients with severe chronic heart failure treated with large ous related compounds have been investigated. Although fixed doses erf either captopril or enalapril, clinically im­ these agents have demonstrated both short- and long­ portant symptomatic was noted more often term hemodynamic benefits in CHF, there are concerns in the enalapril group.52 Hypotension associated with that they can provoke ventricular arrhythmias, adversely enalapril treatment was the most common cause of with­ affect consumption, accelerate progression of the drawal in the CONSENSUS study.38 For this reason, it underlying disease, and increase overall mortality.57 Mil­ was recommended that patients should be observed for at rinone, the second of the class of agents, has been asso­ least 2 hours after administration of the initial dose of ciated with a higher mortality rate than digoxin in a enalapril.53 A significant (P < .05) decline in creatinine comparative trial.58 In the recent Prospective Random­ clearance was also observed with enalapril, but not with ized Survival Evaluation (PROMISE) trial, captopril, confirming earlier findings that the risk of mortality increased by 30% in patients treated with mil­ reducing glomerular filtration rate may be minimized rinone compared with those in the placebo group.59 with captopril but may increase with enalapril in suscep­ Patients in both areas of the study received concomitant tible patients.54 digoxin, diuretics, and ACE inhibitor therapy. Whether Other clinical studies of patients with heart failure these problems can be overcome with the newer phos­ have also reported adverse changes in renal function phodiesterase inhibitors now entering development re­ associated with long-acting ACE inhibitors.38-49-55 Be­ mains to be evaluated. cause increased incidence of side effects, such as hypo­ Several investigators have suggested that low doses tension and renal function changes, may be associated of /3-blockers may provide improvement in symptoms of with the longer-acting ACE inhibitors, treatment with chronic heart failure owing to their potential for revers­ shorter-acting agents such as captopril may be more ing the downregulation of myocardial /3-rcccptors and by beneficial in certain patients. It has therefore been sug­ blocking the potentially harmful effects of circulating

312 The Journal of Family Practice, Vol. 35, No. 3, 1992 ACE Inhibitors in Congestive Heart Failure Kantner

catecholamines. The use of /3-blockcrs in heart failure is ment of congestive heart failure. Cardiovasc Rev Rep 1988; 9:26- being investigated in multicenter trials, but these agents 30. must be used with extreme caution because of their risk 7. Cohn JN, Levine TB, Francis GS, et al. Neurohumoral control mechanisms in congestive heart failure. Am Heart ] 1981; 102: of worsening heart failure. 509-14. 8. Angiotensin-converting-enzvme inhibitors in treatment of heart failure [editorial]. Lancet 1985; 2:811-2. 9. Levine TB, Francis GS, Goldsmith SR, et al. Activity o f the Summary sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relationship to hemodynamic Historically, the principal pharmacological treatments abnormalities in congestive heart failure. Am J Cardiol 1982; 49:1659-66. for CHF have been diuretics and digitalis glycosides. 10. Goldsmith SR, Francis GS, Cowley AW, et al. Increased plasma Both of these groups of agents have proven useful in vasopressin levels in patients with congestive heart failure. patients with CHF, but they may also have limitations. J Am Coll Cardiol 1983; 1:1385-90. 11. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as Diuretics improve symptoms but stimulate the RAA a guide to prognosis in patients w ith chronic congestive heart system and arc associated with a number of adverse failure. N Engl J Med 1984; 311:819-23. biochemical effects. Digitalis has an important inotropic 12. Parmlev WW. Physiology and current therapy of congestive heart failure. J Am Coll Cardiol 1989; 13:777-85. action but may be arrhythmogcnic in some patients at 13. Packer M. Therapeutic options in the management of chronic risk. Digitalis may be most beneficial in the more severe heart failure: is there a drug of first choice? Circulation 1989; grades of CHF or in those CHF patients with atrial 79:198-204. 14. Packer M, Gottlieb SS, Kessler PD. Hormone-electrolyte interac­ arrhythmias. tions in the pathogenesis o f lethal cardiac arrhythmias in patients In recent years, ACE inhibitors have been shown to with congestive heart failure. Am J Med 1986; 80(suppl 4A): be extremely useful agents in the management of CHF. 23-9. 15. Bayliss J, Norell M, Canepa-Anson R, et al. Untreated heart Studies have shown that ACE inhibition can (1) provide failure: clinical and neuroendocrine effects o f introducing diuretics. long-term hemodynamic benefits, (2) blunt both the Br Heart J 1987; 57:17-22. overstimulation of neurohormoncs associated with CHF 16. Ikram H, Chan W, Espiner EA, Nicholls MG. Haemodynamic and hormone responses to acute and chronic furosemide therapy in and the stimulating effects of diuretics on the RAA congestive heart failure. Clin Sci 1980; 59:443-9. system, and (3) reduce the potential for ventricular ar­ 17. The Captopril-Digoxin Multicenter Research Group. Comparative rhythmias in some patients by offsetting potassium loss. effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JAMA 1988; 259:539-14. Studies to date indicate that ACE inhibition is associated 18. Marcus FL. Use of digitalis in acute myocardial infarction. Circu­ with reduction of symptoms and increased survival in lation 1980; 62:17-9. patients with CHF. In mild to moderate CHF, ACE 19. Lee DC S, Johnson RA, Bingham JB, et al. Heart failure in outpatients. A randomized trial of digoxin versus placebo. N Engl inhibitors are most clinically beneficial when used in J Med 1982; 306:699-705. conjunction with diuretic therapy, with or without dig­ 20. Guyatt GH, Sullivan MJJ, Fallen EL, et al. A controlled trial of italis. The early addition of an ACE inhibitor to heart digoxin in congestive heart failure. Am J Cardiol 1988; 61:371 —5. 21. Fleg JL, Gottlieb SH, Lakatta EG. Is digoxin really important in failure therapy may improve both the quality of life and treatment of compensated heart failure? A placebo-controlled survival in a significant proportion of patients with CHF. crossover study in patients with sinus rhythm. Am J Med 1982; 73:244-50. 22. Fleg JL, Ruthfeld B, Wright J, et al. Does digoxin enhance exercise left ventricular function in patients with congestive heart failure Acknowledgment [abstract]? J Am Coll Cardiol 1987; 9:132A. 23. Aronow WS, Starling L, Etienne F. Lack of efficacy of digoxin in This work was supported by an educational grant from Bristol-Myers treatment of compensated congestive heart failure with third heart Squibb. sound and sinus rhythm in elderly patients receiving diuretic therapy. Am J Cardiol 1986; 58:168-9. 24. Johnston GD, McDevitt DG. Is maintenance digoxin necessary in patients with sinus rhythm? Lancet 1979; 1:567-70. References 25. Steiness E, Olesen KH. Cardiac arrhythmias induced by hypokale­ mia and potassium loss during maintenance digoxin therapy. Br 1. Faxon DP. ACE inhibition for the failing heart: experience with Heart J 1976; 38:167-72. captopril. Am Heart J 1988; 115:1085-93. 26. Higginbotham MB. ACE inhibitor treatment of mild to moderate 2. Packer M. Prolonging life in patients with congestive heart failure: congestive heart failure. Prim Cardiol 1990; 16:28-39. the next frontier. Circulation 1987; 75(suppl IV):IV-l-IV-3. 27. Chung EK. Unusual form of digitalis-induced triple A-V nodal 3. Smith WM. of congestive heart failure. Am J Car­ rhythm. Am Heart J 1970; 79:250-3. diol 1985; 55:3A-8A. 28. Smith TW. Digitalis. Mechanisms of action and clinical use. N 4. Massie BM, Conway M. Survival of patients with congestive heart Engl J Med 1988; 318:358-65. failure: past, present, and future prospects. Circulation 1987; 29. Byington R, Goldstein S. Association of digitalis therapy with 75(suppl IY):IV-11-IV-19. mortality in survivors of acute myocardial infarction: observations 5. Geltman EM. Mild heart failure. Diagnosis and treatment. Am in the Beta-Blocker Heart Attack Trial. J Am Coll Cardiol 1985; Heart J 1989; 118:1277-91. 6:976-82. 6. Gorlin R. Angiotensin converting enzyme inhibitors in the treat­ 30. Moss AJ, Davis HT, Conard DL, et al. Digitalis-associated cardiac

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mortality after mvocardial infarction. Circulation 1981; 64: asymptomatic left ventricular dysfunction, following myocardial 1150-6. infarction. Eur Heart J 1990; li(suppl B): 147—56. 31. Kuleck DL, Rahemtolla S. Current role o f digitalis therapy in 46. Pfeffer MA. Move LA, Braunwald E, et al. Selection bias in the use patients with congestive heart failure. JAMA 1991; 265:2995-7. of thrombolytic therapy in acute mvocardial infarction. JAMA 32. Ader R. Chatterjee K, Ports T, et al. Immediate and sustained 1991; 266:528-32. hemodynamic and clinical improvement in chronic heart failure by 47. The SOLV'D Investigators. Effect of enalapril on survival in pa­ an oral angiotensin-converting . Circulation tients with reduced left ventricular ejection fractions and conges­ 1980; 61:931-7. tive heart failure. N Engl J Med 1991; 325:293-302. 33. Clciand JGF, Dargic HJ, Hodsman GP, et al. Captopril in heart 48. Dzau VJ, Colucci YYrS, Williams GH, et al. Sustained effectiveness failure. 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314 The Journal of Family Practice, Vol. 35, No. 3, 1992